Summary. Depression is an usual finding in patients suffering from chronic hepatitis C. Development of moderate to severe depressive symptoms occurs frequently during pegylated interferon/ribavirin treatment and is generally predicted by baseline depression scores. Furthermore, the obese patients have been found to be twice as likely to suffer from anxiety, impaired social interaction, and depression when compared with the no obese population. In order to evaluate the efficacy of a pharmacological treatment of depression, 68 obese patients with chronic hepatitis C, under or not antiviral therapy, were selected and enrolled into this open, controlled pilot study. Our population was divided in two groups: ‘on Selective Serotonin Reuptake Inhibitors plus support’, with individual titration of medication to adequate side-effects, including thirty seven patients, and ‘on only support’, involving thirty one patients. Both groups were well balanced for gender, age and antiviral treatment. The selected patients had, at entry, a Beck Depression Inventory score of 24.5 ± 8.1 (mean ± SD). Therapeutic successful outcomes (a decreased score of ≥ 10 units compared to the baseline) were statistically more frequent in antidepressant drug-treated group (P = 0.005); they were well predicted by dose of Selective Serotonin Reuptake Inhibitors. Thirty five percent of patients were non-responder to Selective Serotonin Reuptake Inhibitors. The drug tolerability was good. Nearly twenty percent of patients were responder to only support.